Process for the preparation of 2 substituted tetrahydropyranols

ABSTRACT

The present invention relates to a process for the preparation of 2-substituted 4-hydroxy-4-methyltetrahydropyrans by reacting 3-methylbut-3-en-1-ol(isoprenol) with the corresponding alkenealdehydes in the presence of a strongly acidic ion exchanger with subsequent hydrogenation. Specifically, the present invention relates to a corresponding process for the preparation of 2-isobutyl-4-hydroxy-4-methyltetrahydropyran by reacting isoprenol with prenal, with subsequent hydrogenation.

CROSS-REFERENCE TO RELATED APPLICATIONS

This Application claims the benefit of U.S. Provisional Application61/348,756 filed on May 27, 2010 which is incorporated by reference.

BACKGROUND OF THE INVENTION

The present invention relates to a process for the preparation of2-substituted 4-hydroxy-4-methyltetrahydropyrans by reacting3-methylbut-3-en-1-ol(isoprenol) with the corresponding alkenealdehydesin the presence of a strongly acidic ion exchanger with subsequenthydrogenation. Specifically, the present invention relates to acorresponding process for the preparation of2-isobutyl-4-hydroxy-4-methyltetrahydropyran by reacting isoprenol withprenal, with subsequent hydrogenation.

Tetrahedron Letters No. 51, pages 4507-4508, 1970 describes the reactionof 3-alken-1-ols with aldehydes and their use for producing the aromachemicals rose oxide and dihydrorose oxide. Also mentioned here is thereaction of 3-methylbutanal with isoprenol under acidic conditions.

SU 825 528 discloses a process for the preparation of di- andtetrahydropyrans and tetrahydropyranols by reacting2-methylbuten-1-ol-4(isoprenol) with aldehydes or ketones in thepresence of an acidic catalyst, where the acidic catalyst is used in anamount of from 0.0001 to 0.01% by weight, based on the amount ofisoprenol, and the reaction is carried out at a temperature of from 0 to25° C. in an organic solvent. The catalysts specified are the ionexchange resin KU-2 (sulfonated polystyrene resin), para-toluenesulfonic acid, sulfuric acid or perchloric acid. By way of example, thereaction of isoprenol with isobutyraldehyde in the presence of KU-2,inter alia, is described.

EP 1 493 737 A1 discloses a process for the preparation of mixtures ofethylenically unsaturated 4-methyl- and 4-methylenepyrans and thecorresponding hydroxypyrans by reacting the corresponding aldehydes withisoprenol, where the reaction is initiated in a reaction system in whichthe molar ratio of aldehyde to isoprenol is greater than 1, i.e. thealdehyde is used in excess. Moreover, the document discloses thesubsequent dehydrogenation of said mixtures to give the desiredethylenically unsaturated pyrans. Suitable catalysts specified for thefirst reaction step are mineral acids, such as hydrochloric acid orsulfuric acid, but preferably methanesulfonic acid or para-toluenesulfonic acid.

JP 2007-154069 relates to 2-substituted 4-hydroxytetrahydropyrans with acontent of the cis-diastereomer of from 70 to 95% by weight. Moreover,the document discloses a process for the preparation of same, byreacting isoprenol with a corresponding aldehyde in the presence of anaqueous solution of an acidic catalyst. Here, the reaction has to becarried out at a concentration of the aqueous catalyst solution eitherin the range from 1:10% by weight at a temperature of from 0 to 100° C.,or in the region of 10% by weight or above at a temperature of from 0 to30° C. The possible acidic catalysts mentioned are generally also ionexchange resins.

BRIEF SUMMARY OF THE INVENTION

Starting from this prior art, the object of the present invention was toprovide a process for the preparation of 2-substituted4-hydroxy-4-methyltetrahydropyrans, in particular of2-isobutyl-4-hydroxy-4-methyltetrahydropropan(=pyranol), which can becarried out in a manner which is easy to handle in terms of processingand with high overall yield for the highest possible chemoselectivity onan industrial scale. In the process, it should be possible to useinexpensive, easy-to-recover and readily reusable starting compounds andreagents and/or catalysts.

Surprisingly, the object was achieved according to the invention throughthe provision of a process for the preparation of 2-substituted4-hydroxy-4-methyltetrahydropyrans of the formula (I)

where the radical

-   -   R₁ is a straight-chain or branched alkyl radical having 1 to 5        carbon atoms,    -   R₂ is hydrogen or a straight-chain or branched alkyl radical        having 1 to 3 carbon atoms,

comprising the reaction of 3-methylbut-3-en-1-ol of the formula (II)

with an aldehyde of the formula (III)

where the radicals R₁ and R₂, independently of one another, have thesame meanings as given in formula (I), in the presence of water and inthe presence of a strongly acidic cation exchanger to form the compoundof the formula (IV)

and hydrogenation of the compound of the formula (IV) in the presence ofa catalyst to give a compound of the formula (I).

DETAILED DESCRIPTION OF THE INVENTION

Suitable starting materials for carrying out the process according tothe invention are 3-methylbut-3-en-1-ol(isoprenol) of the formula (II),

which is readily accessible by known processes from isobutene andformaldehyde on any scale and is commercially readily available. Noparticular requirements are placed on the purity, quality or preparationprocess of the isoprenol to be used according to the invention. It canbe used as starting material in the course of the process according tothe invention in standard commercial quality and purity with goodsuccess. Preference is given to using isoprenol which has a purity of90% by weight or above, particularly preferably one with a purity offrom 95 to 100% by weight and very particularly preferably one with apurity of from 97 to 99.9% by weight or even more preferably 98 to 99.8%by weight.

A further suitable starting material for carrying out the processaccording to the invention is an alkenealdehyde of the formula (III)

where the radical R₁ may be a straight-chain or branched alkyl radicalhaving 1 to 5 carbon atoms and R₂ may be hydrogen or a straight-chain orbranched alkyl radical having 1 to 3 carbon atoms.

An alkyl substituent R₁ is to be understood as meaning one which has 1to 5 carbon atoms, such as, for example, methyl, ethyl, n-propyl,isopropyl, n-butyl, sec-butyl, tert-butyl or n-pentyl, preferablymethyl, ethyl, n-propyl, isopropyl, and very particularly preferablymethyl.

An alkyl substituent R₂ is to be understood as meaning one which has 1to 3 carbon atoms, such as, for example, methyl, ethyl, n-propyl orisopropyl, preferably methyl or ethyl, and very particularly preferablymethyl.

In the process according to the invention, the words “strongly acidiccation exchanger” mean that the ion exchanger is present in H⁺ form.

According to the invention, very particularly preferred alkenealdehydesof the formula (III) are those in which the radical R₁ is astraight-chain or branched alkyl radical having 1 to 3 carbon atoms andthe radical R₂ is an alkyl radical having 1 to 2 carbon atoms. Accordingto the invention, preferred meanings for the radical R₁ are therefore,for example, methyl, ethyl, n-propyl and isopropyl, very particularlypreferably methyl and preferred meanings for the radical R₂ aretherefore methyl or ethyl and very particularly preferably methyl. Asalkenealdehydes of the formula (III) accordingly to be used preferablyaccording to the invention, the following may be mentioned:prenal(3-methyl-2-butenal), 2-butenal, 3-methyl-2-pentenal, 2-pentenal,2-hexenal, 3-methyl-2-hexenal. An alkenealdehyde of the formula (III) tobe used very particularly preferably according to the invention isprenal.

The starting materials isoprenol and the aldehyde of the formula (III)selected in each case to be used in the course of the process accordingto the invention can be reacted together in various quantitative ratios.Thus, it is possible to use one of the two starting materials in excess,in which case the level of the selected excess should vary withinoperationally and economically advantageous limits, but otherwise can inprinciple be freely chosen. Following the stoichiometry of the reactionaccording to the invention of isoprenol with the selected aldehyde ofthe formula (III), isoprenol and the aldehyde of the formula (III),preferably prenal, are used in a molar ratio in the range from 1:2 to2:1, corresponding to a double molar excess of one of the startingmaterials. Within the context of a preferred embodiment, the processaccording to the invention is carried out in such a way that isoprenoland the aldehyde of the formula (III) are used in a molar ratio of from0.7:1 to 2:1. The process according to the invention is particularlypreferably carried out in such a way that isoprenol and the aldehyde ofthe formula (III) are used in a molar ratio of from 1:1 to 2:1. Theprocess according to the invention is very particularly preferablycarried out in such a way that isoprenol and the aldehyde of the formula(III) are used in a molar ratio of from 1:1 to 1.5:1.

The reaction of isoprenol with the selected aldehyde of the formula(III), preferably with prenal, that is to be carried out in the courseof the process according to the invention for the preparation of the2-substituted 4-hydroxy-4-methyltetrahydropyrans of the formula (I),preferably for the preparation of2-isobutyl-4-hydroxy-4-methyltetrahydropyran, is carried out in thepresence of water. This means that besides isoprenol, the aldehyde ofthe formula (III) and the selected strongly acidic cation exchanger,water is also added to the reaction mixture. In addition, the reactionmixture can also comprise small amounts of water which can be releasedby the dehydration of the desired process product of the formula (I)which possibly takes place as an undesired secondary reaction.

The reaction of the isoprenol with the selected aldehyde of the formula(III) is usually carried out in the presence of about at least 10 mol %of water, where the amount of water refers to the amount of the startingmaterial isoprenol, optionally used in deficit, or to the aldehyde ofthe formula (III), or, in the case of the equimolar reaction of the twostarting materials, to the quantitative amount of one of the two.

Above the stated value, the amount of water can be freely chosen and islimited only by processing or cost aspects, if at all, and can be usedperfectly well in a large excess, for example in 10- to 100-fold excessor even more. Preferably, a mixture of isoprenol and the selectedaldehyde of the formula (III), preferably prenal, is prepared with theselected amount of water such that the added water remains dissolved inthe mixture of isoprenol and the selected aldehyde, i.e. no two-phasesystem is present.

Usually, in the course of the process according to the invention, thestarting materials isoprenol and the selected aldehyde of the formula(III) are reacted in the presence of at least 25 mol %, preferably of atleast 50 mol %, even more preferably of at least 75 and even morepreferably of at least 90 to about 1000 mol %, of water, where theamount of water refers to the amount of the starting material isoprenol,optionally used in deficit, or to the aldehyde of the formula (III), or,in the case of the equimolar reaction of the two starting materials, tothe quantitative amount of one of the two.

Within the context of a preferred embodiment, the reaction to be carriedout according to the invention is carried out such that it is carriedout in the presence of an at least equimolar amount of water, where theamount of water refers to the amount of the starting material isoprenol,optionally used in deficit, or to the aldehyde of the formula (III), or,in the case of the equimolar reaction of the two starting materials, tothe quantitative amount of one of the two. Consequently, the reactionaccording to the invention of isoprenol with the selected aldehyde ofthe formula (III) is preferably carried out in the presence of from 100to 250 mol %, particularly preferably 100 to 230 mol %, even morepreferably 100 to 200 mol % and most preferably in the presence of from100 to 180 mol %, of water, where the amount of water refers to theamount of the starting material isoprenol, optionally used in deficit,or to the aldehyde of the formula (III), or, in the case of theequimolar reaction of the two starting materials, to the quantitativeamount of one of the two.

The specified starting materials, i.e. isoprenol and the aldehydeselected in each case and the water to be used in the above amount canbe brought into contact with one another or be mixed in any desiredorder. Usually, a mixture of isoprenol and the selected aldehyde of theformula (III) is prepared with the selected amount of water and thismixture is used in the course of the reaction to be carried outaccording to the invention.

The reaction of isoprenol with the selected aldehyde of the formula(III) to be carried out in the course of the process according to theinvention for preparing the desired 2-substituted4-hydroxy-4-methyltetrahydropyrans of the formula (I), is carried out inthe presence of a strongly acidic cation exchanger. Within the contextof the present invention, the term strongly acidic cation exchanger isto be understood as meaning those cation exchangers which have stronglyacidic groups, usually sulfonic acid groups, whose matrix may begel-like or macroporous.

One preferred embodiment of the process according to the invention isaccordingly one in which a strongly acidic cation exchanger comprisingor having sulfonic acid groups is used.

Strongly acidic cation exchangers are in particular ion exchange resinsin the H+ form. As such, the following are for example suitable:

-   -   strongly acidic ion exchangers (such as e.g. Amberlyst,        Amberlite, Dowex, Lewatit, Purolite, Serdolit) which are based        on polystyrene, and which comprise copolymers of styrene and        divinylbenzene as carrier matrix with sulfonic acid groups in H+        form,    -   ion exchanger groups functionalized with sulfonic acid groups        (—SO₃H).

The ion exchangers differ in the structure of their polymer backbones,and a distinction is made between gel-like and macroporous resins. Thestrongly acidic ion exchange resins are generally regenerated withhydrochloric acid and/or sulfuric acid.

Nafion® here is perfluorinated ion exchange materials consisting offluorocarbon base chains and perfluorinated side chains which comprisesulfonic acid groups. The resins are prepared by a copolymerization ofperfluorinated, terminally unsaturated andsulfonyl-fluoride-functionilized ethoxylates with perfluoroethene.Nafion® belongs to the gel-like ion exchange resins. One example of sucha perfluorinated polymeric ion exchange resin which may be mentioned isNafion® NR-50.

One particularly preferred embodiment of the process according to theinvention is one in which at least one strongly acidic cation exchangeris used in the H+ form, where the ion exchanger comprises a polymerbackbone having sulfonic acid groups and is either gel-like or comprisesmacroporous resins.

One very particularly preferred embodiment of the process according tothe invention is one in which the ion exchanger is based on apolystyrene backbone with sulfonic acid groups or on a perfluorinatedion exchange resin with sulfonic acid groups.

The commercially available strongly acidic cation exchangers are knownunder the trade names Lewatit® (Lanxess), Purolite® (The PuroliteCompany), Dowex® (Dow Chemical Company), Amberlite® (Rohm and HaasCompany), Amberlyst™ (Rohm and Haas Company).

Strongly acidic cation exchangers preferred according to the inventionthat may be mentioned are, for example: Lewatit® K 1221, Lewatit® K1461, Lewatit® K 2431, Lewatit® K 2620, Lewatit® K 2621, Lewatit® K2629, Lewatit® K 2649, Amberlite® IR 120, Amberlyst™ 131, Amberlyst™ 15,Amberlyst™ 31, Amberlyst™ 35, Amberlyst™ 36, Amberlyst™ 39, Amberlyst™46, Amberlyst™ 70, Purolite® SGC650, Purolite® C100H, Purolite® C150H,Dowex® 50X8, Serdolit® red and Nafion® NR-50.

Within the scope of a preferred embodiment, the reaction of isoprenolwith the selected aldehyde of the formula (III) to be carried outaccording to the invention is carried out in the presence of at leastone strongly acidic cation exchanger which is selected from the group ofthe cation exchangers comprising Lewatit® K 1221, Lewatit® K 2629,Amberlyst™ 131, Puralite® SGC650, Purolite® C100H, Purolite® C150H,Amberlite® IR 120 and Dowex® 50X8.

Strongly acidic cation exchangers that are particularly preferredaccording to the invention are the cation exchangers Amberlyst™ 131and/or Lewatit® K 1221.

A strongly acidic cation exchanger that is very particularly preferredaccording to the invention is Amberlyst™ 131, which, like the otherspecified cation exchangers, is commercially available.

To carry out the reaction according to the invention of isoprenol withthe aldehyde of the formula (III), the specified starting materials andthe selected amount of water, preferably in the form of a mixture, arebrought into contact with the selected strongly acidic cation exchanger.The amount of cation exchanger to be used is not critical and can befreely chosen within wide limits taking into consideration the cost andprocessing aspect. The reaction can accordingly be carried out either inthe presence of catalytic amounts or in the presence of large excessesof the selected strongly acidic cation exchanger. Usually, the selectedcation exchanger is used in an amount of from about 5 to about 40% byweight, preferably in an amount of from about 20 to about 40% by weightand particularly preferably in an amount of from about 20 to about 30%by weight, in each case based on the sum of isoprenol used and aldehydeof the formula (III). Here, the data refer to the ready-to-use cationexchanger, which is usually pretreated with water and accordingly cancomprise amounts of up to about 70% by weight, preferably from about 30to about 65% by weight and particularly preferably from about 40 toabout 65% by weight, of water. Particularly in the case of adiscontinuous procedure, an addition of water beyond this may thereforebe unnecessary when carrying out the process according to the invention.

The specified strongly acidic cation exchangers can be used eitherindividually or in the form of mixtures with one another in the courseof the process according to the invention.

The reaction to be carried out according to the invention can, ifdesired, also be carried out in the presence of a solvent that is inertunder the reaction conditions, such as, for example, tert-butyl methylether, cyclohexane, toluene, hexane or xylene. The specified solventscan be used on their own or in the form of mixtures with one another.Within the context of a preferred embodiment of the process according tothe invention, the reaction of isoprenol with the selected aldehyde ofthe formula (III) is carried out without addition of an organic solvent.

The reaction of isoprenol with the selected aldehyde of the formula(III) to be carried out according to the invention in the presence ofwater and in the presence of a strongly acidic cation exchanger isusually carried out at a temperature in the range from 0 to 100° C.,preferably at a temperature in the range from 20 to 90° C. andparticularly preferably at a temperature in the range from 20 to 80° C.,where the temperature refers to that of the reaction mixture.

The reaction to be carried out according to the invention can, ifdesired, be carried out discontinuously or continuously. Here, forexample in the discontinuous case, the reaction can be undertaken suchthat a mixture of isoprenol, the selected aldehyde of the formula (III)and water is initially introduced into a suitable reaction vessel andthe strongly acidic cation exchanger is added. Following conclusion ofthe reaction, the cation exchanger can then be separated off from theresulting reaction mixture by suitable separation methods, preferably byfiltration or by centrifugation. The order in which the individualreaction components are brought into contact is not critical and can bevaried according to the particular processing embodiment.

Within the context of a preferred embodiment, the reaction of isoprenolwith the selected aldehyde of the formula (III) to be carried outaccording to the invention is carried out continuously. For this, forexample a mixture of the starting materials isoprenol and aldehyde ofthe formula (III) to be reacted can be prepared with water and thismixture can be continuously brought into contact with a strongly acidiccation exchanger. For this, the selected cation exchanger can beintroduced, for example, into a suitable flow reactor, for example astirred reactor with inlet and outlet or a tubular reactor, and thestarting materials and the water can be discharged continuously intothis and the reaction mixture can be continuously discharged. In thisconnection, the starting materials and the water can, if desired, beintroduced into the flow reactor as individual components or else in theform of a mixture as described above.

The hydrogenation step of the process according to the invention ispreferably carried out in the presence of hydrogen and in the presenceof a heterogeneous catalyst, where the heterogeneous catalyst to be usedcomprises 30 to 70% by weight, preferably 40 to 60% by weight, ofoxygen-containing compounds of nickel, calculated as NiO, 15 to 45% byweight, preferably 20 to 40% by weight, of oxygen-containing compoundsof zirconium, calculated as ZrO₂, 5 to 30% by weight, preferably 10 to25% by weight, of oxygen-containing compounds of copper, calculated asCuO, and 0.1 to 10% by weight, preferably 0.5 to 5% by weight, ofoxygen-containing compounds of molybdenum, calculated as MoO₃,optionally alongside further components in an amount of from 0 to 10% byweight, preferably 0 to 5% by weight, such as, for example, graphite.Here, the data in % by weight refer to the dry, nonreduced catalyst.

Within the context of one preferred embodiment of the process accordingto the invention, for the procedure, use is made of those catalystscomprising

45 to 55% by weight of oxygen-containing compounds of nickel, calculatedas NiO,

25 to 35% by weight of oxygen-containing compounds of zirconium,calculated as ZrO₂,

5 to 20% by weight of oxygen-containing compounds of copper, calculatedas CuO, −0.1 to 3% by weight, in particular 1 to 3% by weight ofoxygen-containing compounds of molybdenum, calculated as MoO₃,

0 to 5% by weight of further components,

where the data in % by weight add up to 100% by weight and refer to thedry, nonreduced catalyst. According to the invention, particularpreference is given to those catalysts which consist of theaforementioned components in the likewise aforementioned weightfractions.

One catalyst that is particularly preferred for use within the contextof the process according to the invention consists to 49 to 53% byweight of NiO, to 15 to 19% by weight of CuO, to 28 to 32% by weight ofZrO₂ and to 1 to 2% by weight of MoO₃, and optionally to 0 to 3% byweight of further components, such as, for example, graphite, where theweight fractions selected in each case of the individual components arebased on the dry, nonreduced catalyst and add up to 100% by weight.Catalysts of this type are known and can be prepared for example asdescribed in EP 0 696 572.

The catalysts that can be used according to the invention can beprepared e.g. using precipitation methods. Thus, for example, they canbe obtained through a joint precipitation of the nickel and coppercomponents from an aqueous salt solution comprising these elements bymeans of mineral bases in the presence of a slurry of a sparinglysoluble, oxygen-containing zirconium compound and subsequent washing,drying and calcination of the resulting precipitate. Sparingly soluble,oxygen-containing zirconium compounds which can be used are, forexample, zirconium dioxide, zirconium oxide hydrate, zirconiumphosphates, borates and silicates. The slurries of the sparingly solublezirconium compounds can be prepared by suspending finely particulatepowders of these compounds in water with vigorous stirring. Theseslurries are advantageously obtained by precipitating out the sparinglysoluble zirconium compounds from aqueous zirconium salt solutions bymeans of mineral bases.

Preferably, the catalysts that can be used according to the inventionare prepared via a joint precipitation (coprecipitation) of all of theircomponents. For this, an aqueous salt solution comprising the catalystcomponents is expediently admixed, at elevated temperature and withstirring, with an aqueous mineral base, in particular an alkali metalbase—for example sodium carbonate, sodium hydroxide, potassium carbonateor potassium hydroxide—until the precipitation is complete. The type ofsalts used is generally not critical—since what is primarily importantin this procedure is the water solubility of the salts, a criterion istheir good water solubility required for the preparation of theserelatively highly concentrated salt solutions. It is consideredself-evident that when selecting the salts of the individual components,only salts with those anions which do not lead to disturbances, whetherby causing undesired precipitations or by hindering or preventingprecipitation as a result of complex formation, are naturally chosen.

Catalysts with particularly advantageous properties that can be usedaccording to the invention are obtainable by precipitating some of thezirconium component of the catalyst, expediently from an aqueouszirconium salt solution, separately in a precipitation apparatus byadding aqueous mineral bases. The remainder of the zirconium componentof the catalyst can then be precipitated onto the preferably freshlyprecipitated zirconium oxide hydrate obtained in this way together withthe other catalytically active components in a coprecipitation, as hasbeen described above. In this connection, it has generally proven to beparticularly expedient to preprecipitate 10 to 80% by weight, preferably30 to 70% by weight and in particular 40 to 60% by weight of the totalamount of zirconium in the catalytically active mass.

The catalysts prepared in this way can be stored and used as such. Priorto their use as catalysts in the course of the process according to theinvention, they are usually prereduced. However, they can also be usedwithout prereduction, in which case they are then reduced by thehydrogen present in the reactor under the conditions of thehydrogenation according to the invention. For the prereduction, thecatalysts are generally firstly exposed to a nitrogen/hydrogenatmosphere at 150 to 200° C. over a period of from 12 to 20 hours andthen further treated in a hydrogen atmosphere for up to ca. 24 hours at200 to 300° C. During this prereduction, some of the oxygen-containingmetal compounds present in the catalysts is usually reduced to thecorresponding metals, meaning that these are present together with thevarious oxygen compounds in the active form of the catalyst.

In general, the catalysts according to the invention are preferably usedin the form of unsupported catalysts. The term “unsupported catalyst” isused to refer to a catalyst which, in contrast to a supported catalyst,consists only of catalytically active mass. Unsupported catalysts can beused by introducing the catalytically active mass ground to powder intothe reaction vessel or by arranging the catalytically active massfollowing grinding, mixing with molding auxiliaries, molding andheat-treating as catalyst moldings—for example as beads, cylinders,tablets, rings, spirals, strands and the like—in the reactor.

Within the context of a further embodiment of the hydrogenation processaccording to the invention, the selected heterogeneous catalyst is usedin the form of a fixed-bed catalyst.

To carry out the process according to the invention, the compound of theformula (IV) described above is brought into contact with hydrogen andthe selected catalyst. The hydrogen here can be used in undiluted form,usually in a purity of about 99.9% by volume, or in diluted form, i.e.in the form of mixtures with inert gases, such as, for example, nitrogenor argon. Preferably, hydrogen is used in undiluted form.

The reaction can take place with good success with or without theaddition of a solvent. If the reaction takes place in the presence of asolvent, organic solvents that are inert under the reaction conditionsare suitable, such as, for example, methanol, ethanol, isopropanol,hexane, heptane, cyclohexane and the like. Preferably, the reaction iscarried out in methanol as solvent.

The hydrogenation according to the invention can be carried out at ahydrogen pressure (absolute) in the range from 1 to 200 bar, preferablyfrom 2 or better from 3 to 200 bar, particularly preferably from 4 or 5to 150 bar, particularly preferably from 5 to 100 bar and veryparticularly preferably in the range from 5 to 50 bar. The reactiontemperature chosen here for carrying out the hydrogenation according tothe invention is advantageously a temperature in the range from 20 to150° C., preferably from 40 to 130° C., particularly preferably from 60to 110° C. and very particularly preferably from 70 to 100° C.

In practice, the procedure during the implementation generally involvesfeeding the product of the formula (IV) to be reacted to the catalyst,which is usually located in a fixed-bed reactor preferably heatedexternally, such as, for example, a tubular reactor, autoclave ortube-bundle reactor, at the desired reaction temperature and the desiredpressure. Here, the the catalyst is generally used at a rate of 0.1 to1.0, preferably 0.1 to 0.6 and particularly preferably 0.2 to 0.4 kg ofthe compound of the formula (IV) per kg of catalyst and per hour. Inthis connection, it may be expedient to heat the product of the formula(IV) to be used prior to introduction into the reaction vessel or thereactor, preferably to the reaction temperature.

The hydrogenation process according to the invention can be carried outeither discontinuously or continuously. In both cases, unreactedstarting material can be circulated together with the hydrogen.

One preferred embodiment of the process according to the inventionaccordingly relates to a continuous process for the preparation of2-substituted 4-hydroxy-4-methyltetrahydropyrans of the formula (I)comprising the steps

-   -   a. providing a flow reactor comprising the selected strongly        acidic cation exchanger;    -   b. continuously introducing isoprenol, the aldehyde of the        formula (III) and water into the flow reactor;    -   c. continuously bringing isoprenol, the aldehyde of the        formula (III) and water into contact with the strongly acidic        cation exchanger in the flow reactor to give a reaction mixture        comprising the desired compound of the formula (IV)    -   d. continuously hydrogenating the reaction mixture comprising        the compound of the formula (IV), and    -   e. continuously discharging the reaction mixture from the flow        reactor.

The selected strongly acidic cation exchanger may be present here eitherin the form of a loose bed or in the form of a fixed bed in theaforementioned flow reactor.

It is also possible to carry out the reaction of isoprenol with thealdehyde of the formula (III) to be carried out according to theinvention in a cascade of a plurality of, for example 2 or 3,successively connected flow reactors, where the individual flow reactorsmay also be filled with various strongly acidic cation exchangers and ifusing tubular reactors, these can be operated either in liquid phasemode or trickle mode. Moreover, the reaction mixture discharged from theselected flow reactor can, if desired, also be returned in part back tothe continuously operated reaction.

The process according to the invention permits the preparation of2-substituted 4-hydroxy-4-methyltetrahydropyrans of the formula (I),specifically the preparation of2-isobutyl-4-hydroxy-4-methyltetrahydropyrans of the formula (I). Theseare usually produced in the form of reaction mixtures which, besides thedesired target compounds, can also comprise radicals of the startingmaterials used, the water used and also possibly, to a slight extent,also the dehydrated by-products of the formulae (Va) and (Vb)

where R₁ and R₂ may have the meanings given under formula (I). Theprocess according to the invention permits the preparation of thedesired hydroxypyrans of the formula (I) or preferably of2-isobutyl-4-hydroxy-4-methyltetrahydropyran in high yield and highpurity, where the undesired dehydration products of the formulae (Va) to(Vb) are only produced to a minor extent, if at all.

Just like the unreacted starting compounds and/or the starting compoundsused in excess, these by-products can be advantageously returned againto the reaction.

The reaction mixtures obtained according to the invention typicallyconsist to an extent of about 50 to about 90% by weight, often to about60 to about 80% by weight, of the desired 2-substituted4-hydroxy-4-methyltetrahydropyrans of the formula (I) and only up toabout 20% by weight, preferably only up to about 15% by weight andparticularly preferably only up to 10% by weight, of the dehydrationproducts of the formulae (IVa) to (IVc), in each case based on the totalweight of the crude product obtained and moreover of the unreactedstarting materials and/or starting materials used in excess, and theother specified by-products.

The substance mixtures obtained as crude product can be further purifiedeasily by methods known to the person skilled in the art, in particularby distillation and/or rectification. In this way, the 2-substituted4-hydroxy-4-methyltetrahydropyran of the formula (I) desired in eachcase, in particular when using isoprenol and prenal with subsequenthydrogenation, the desired 2-isobutyl-4-hydroxy-4-methyltetrahydropyranis obtained in a purity of more than 95% by weight or preferably from 97to 99.9% by weight or particularly preferably from 98 to 99.8% byweight, i.e. in a quality as is required, for example, for use as aromachemical.

One preferred embodiment of the process according to the inventionrelates to the preparation of 2-substituted4-hydroxy-4-methyltetrahydropyrans in the form of mixtures of thecis-diastereomers of the formula (Ib)

and of the trans-diastereomers of the formula (Ic)

where the diastereomer ratio of the cis-diastereomer of the formula (Ib)to the trans-diastereomer of the formula (Ic) is 65:35 to 95:5,preferably 70:30 to 85:15.

In particular for the reaction of isoprenol with prenal with subsequenthydrogenation preferred according to the invention, in the course of theprocess according to the invention2-isobutyl-4-hydroxy-4-methyltetrahydropyran is obtained in the form ofmixtures of the cis-diastereomer of the formula (Ib)

and of the trans-diastereomers (Ic)

where the diastereomer ratio of the cis-diastereomer of the formula (Ib)to the trans-diastereomer of the formula (Ic) is 65:35 to 95:5,preferably 70:30 to 85:15. On account of their particular odorproperties, mixtures of this type are suitable to a particular degreefor use as aroma chemicals, for example as component with lily of thevalley scent for producing fragrance compositions.

Within the context of one preferred embodiment, the present inventiontherefore provides a process for the preparation of2-isobutyl-4-hydroxy-4-methyltetrahydropyran of the formula (1a)

comprising the reaction of 3-methylbut-3-en-1-ol of the formula (II)with prenal of the formula (IIIa)

in the presence of water and in the presence of a strongly acidic cationexchanger to form the product of the formula (IVa)

and subsequent catalytic hydrogenation in the presence of hydrogen and anickel-containing catalyst to form the compound of the formula (Ia).

The examples below serve to illustrate the invention without limiting itin any way:

Gas chromatographic analyses were carried out in accordance with thefollowing method: 30 m DB-WAX, ID.: 0.32 mm, FD.: 1.2 μm; 50° C., 3°C./min-170° C., 20° C./min to 240° C.; t_(R)=min; carrier gas: He;sample: 0.2 μl; t_(R) (prenal): 9.1; t_(R) (isoprenol): 10.6; t_(R)(dehydrorose oxide of the formula (Va)): 15.6; t_(R) (nerol oxide of theformula Vb)): 18.5; t_(R) (trans-pyranol of the formula (Ic)): 28.5;t_(R) (cis-pyranol of the formula (1b)): 29.8; t_(R) (trans-hydroxyroseoxide of the formula Iva): 34.2; t_(R) (cis-hydroxyrose oxide of theformula Iva): 35.4; t_(R)(2-(2-hydroxymethylpropyl)-4-methyltetrahydropyranol): 41.5 and 42.2.

EXAMPLE 1 Preparation of Trans- and Cis-Hydroxyrose Oxide

Prior to use, the ion exchanger was firstly washed several times withwater, then once with methanol and finally washed free of methanol withwater.

1.7 g of Amberlyst™ 131 (58% by weight H₂O) and 4.2 g (0.05 mol) ofisoprenol were introduced as initial charge in a flask at roomtemperature and then 4.3 g (0.05 mol) of prenal were added dropwise. Thereaction mixture was stirred for 3 h at room temperature. The fullyreacted reaction mixture was admixed with 30 ml of MTBE and the ionexchanger was then filtered off. The ion exchanger was washed twice within each case 5 ml of MTBE. The resulting reaction solution was analyzedby gas chromatography (in GC area %). The yellow filtrate wasconcentrated on a rotary evaporator, giving 7.1 g of crude product.

prenal 1.8 GC area % isoprenol 3.8 GC area % dehydrorose oxide 1.6 GCarea % nerol oxide 4.5 GC area % trans-hydroxyrose oxide 17.7 GC area %cis-hydroxyrose oxide 67.5 GC area %

EXAMPLE 2 Preparation of Trans- and Cis-Hydroxyrose Oxide

1.7 g (20% by weight) of Amberlyst™ 131 (58% by weight H₂O) and 4.2 g(0.05 mol) of isoprenol were introduced as initial charge in a flask atroom temperature and then 4.3 g (0.05 mol) of prenal were addeddropwise. The reaction mixture was stirred for 1 h at 60° C. Aftercooling the fully reacted reaction mixture MTBE (30 ml) was added andthe ion exchanger was then filtered off. The ion exchanger was washedtwice with in each case 5 ml of MTBE. The resulting reaction solutionwas analyzed by gas chromatography (in GC area %). The yellow filtratewas concentrated on a rotary evaporator, giving 7.6 g of crude product.

prenal 0.9 GC area % isoprenol 1.2 GC area % dehydrorose oxide 1.8 GCarea % nerol oxide 4.5 GC area % trans-hydroxyrose oxide 31.1 GC area %cis-hydroxyrose oxide 55.5 GC area % 2-(2-hydroxymethylpropyl)- 2.7 GCarea % 4-methyltetrahydropyranol

EXAMPLE 3 Preparation of Trans- and Cis-Hydroxyrose Oxide

1.7 g (20% by weight) of Amberlyst™ 131 (58% by weight H₂O) and 4.2 g(0.05 mol) of isoprenol were introduced as initial charge in a flask atroom temperature and then 4.3 g (0.05 mol) of prenal were addeddropwise. The reaction mixture was stirred for 1 h at 80° C. Aftercooling the fully reacted reaction mixture, MTBE (30 ml) was added andthe ion exchanger was then filtered off. The ion exchanger was washedtwice with in each case 5 ml of MTBE. The resulting reaction solutionwas analyzed by gas chromatography (GC area %). The yellow filtrate wasconcentrated on a rotary evaporator, giving 7.6 g of crude product.

prenal 0.4 GC area % isoprenol 0.3 GC area % dehydrorose oxide 1.7 GCarea % nerol oxide 4.9 GC area % trans-hydroxyrose oxide 46.1 GC area %cis-hydroxyrose oxide 27.3 GC area % 2-(2-hydroxymethylpropyl)- 13.5 GCarea % 4-methyltetrahydropyranol

EXAMPLE 4 Preparation of Trans- and Cis-Pyranol

In a 300 ml laboratory autoclave, 20 g of hydroxyrose oxide dissolved in80 ml of methanol were hydrogenated in the presence of 20 g of acatalyst consisting of 50% by weight of NiO, 17% by weight of CuO, 30.5%by weight of ZrO₂ and 1.5% by weight of MoO₃ in the form of tablets witha diameter and a height of in each case 3 mm at a hydrogen pressure of30 bar and a temperature of 95° C. with vigorous stirring. After areaction time of 4 h, the catalyst was filtered off. The resultingreaction mixture was analyzed by gas chromatography at the times givenin Table 1. This gave the results given in Table 1 (in each case in GCarea %, conversion: 99% and selectivity: 95%).

TABLE 1 Time (h) 0 2 4 trans-hydroxyrose oxide 55.5 4.5 0.4cis-hydroxyrose oxide 36.4 2.9 0.3 trans-pyranol 0 55.4 57.6 cis-pyranol0 34.0 36.3

The invention claimed is:
 1. A process for the preparation of2-substituted 4-hydroxy-4-methyltetrahydropyrans of the formula (I)

where the radical R₁ is a straight-chain or branched alkyl radicalhaving 1 to 5 carbon atoms, and R₂ is hydrogen or a straight-chain orbranched alkyl radical having 1 to 3 carbon atoms, which comprisesreacting 3-methylbut-3-en-1-ol of the formula (II)

with an aldehyde of the formula (III)

wherein the radicals R₁ and R₂ have the same meanings as given informula (I), in the presence of water and in the presence of a stronglyacidic cation exchanger to form the compound of the formula (IV)

and hydrogenation of the compound of the formula (IV) to give a compoundof the formula (I), wherein the hydrogenation is carried out in thepresence of hydrogen and a catalyst comprising 30 to 70% by weight ofoxygen-containing compounds of nickel, calculated as NiO, 15 to 45% byweight of oxygen-containing compounds of zirconium, calculated as ZrO₂,5 to 30% by weight of oxygen-containing compounds of copper, calculatedas CuO and 0.1 to 10% by weight of oxygen-containing compounds ofmolybdenum, calculated as MoO₃, optionally 0 to 10% by weight of furthercomponents, where the data in % by weight refer to the dry, nonreducedcatalyst.
 2. The process according to claim 1, wherein the radical R₁ isa straight-chain or branched alkyl radical having 1 to 3 carbon atoms.3. The process according to claim 1, wherein the radical R₂ is methyl orethyl.
 4. The process according to claim 1, wherein3-methylbut-3-en-1-ol of the formula (II) and the aldehyde of theformula (III) are used in a molar ratio of from 0.7:1 to 2:1.
 5. Theprocess according to claim 1, wherein R₁ and R₂ are methyl and wherein 3methylbut-3-en-1-ol of the formula (II) and the aldehyde of the formula(III) are used in a molar ratio of from 1:1 to 1.5:1.
 6. The processaccording to claim 1, wherein the reaction of 3 methylbut-3-en-1-ol ofthe formula (II) with an aldehyde of the formula (III) is carried outwithout addition of an organic solvent.
 7. The process according toclaim 1, wherein the reaction of 3 methylbut-3-en-1-ol of the formula(II) with an aldehyde of the formula (III) is carried out at atemperature in the range from 20 to 80° C.
 8. The process according toclaim 1, wherein the reaction of 3 methylbut-3-en-1-ol of the formula(II) with an aldehyde of the formula (III) is carried out continuously.9. The process according to claim 1, wherein the reaction of 3methylbut-3-en-1-ol of the formula (II) with the aldehyde of the formula(III) is carried out in the presence of methanol.
 10. The processaccording to claim 1, wherein the catalyst is used in the form of anunsupported catalyst.
 11. The process according to claim 1, wherein thecatalyst is used in the form of a fixed-bed catalyst.
 12. The processaccording to claim 1, wherein the hydrogenation is carried out at atemperature in the range from 50 to 130° C.
 13. The process according toclaim 1, wherein the hydrogenation is carried out at a hydrogen pressurein the range from 5 to 200 bar absolute.
 14. The process according toclaim 1, wherein the hydrogenation is carried out continuously.
 15. Theprocess according to claim 1, wherein the reaction of 3methylbut-3-en-1-ol of the formula (II) with the aldehyde of the formula(III) is carried out in the presence of an organic solvent.
 16. Theprocess according to claim 1, comprising the steps a. providing a flowreactor comprising the strongly acidic cation exchanger; b. continuouslyintroducing 3 methylbut-3-en-1-ol of the formula (II), the aldehyde ofthe formula (III) and water into the flow reactor; c. continuouslybringing 3 methylbut-3-en-1-ol of the formula (II), the aldehyde of theformula (III) and water into contact with the strongly acidic cationexchanger in the flow reactor to give a reaction mixture comprising thecompound of formula (IV), d. continuously hydrogenating the reactionmixture comprising the compound of the formula (IV), and e. continuouslydischarging the reaction mixture from the flow reactor.
 17. The processaccording to claim 1 for the preparation of 2-substituted4-hydroxy-4-methyltetrahydropyrans of the formula (I) in the form ofmixtures of the cis-diastereomer of the formula (Ib)

and of the trans-diastereomer of the formula (Ic)

wherein the diastereomer ratio of the cis-diastereomer of the formula(Ib) to the trans-diastereomer of the formula (Ic) is 65:35 to 95:5. 18.The process according to claim 9, wherein the catalyst comprises: 40 to60% by weight of oxygen-containing compounds of nickel, calculated asNiO, 20 to 40% by weight of oxygen-containing compounds of zirconium,calculated as ZrO₂, 10 to 25% by weight of oxygen-containing compoundsof copper, calculated as CuO and 0.5 to 5% by weight ofoxygen-containing compounds of molybdenum, calculated as MoO₃, andoptionally 0 to 5% by weight of further components.